Process for preparing pyridine and quinoline derivatives

ABSTRACT

The present invention pertains to a method of preparing substituted and unsubstituted N-hydroxy-2-aminobutane diacid derivatives which can be dehydrated to 2-aminobut-2-ene dioic acid derivatives, which can be subsequently converted to pyridine and quinoline derivatives.

This application is a continuation-in-part of application Ser. No.07/507,330 of Elango et al., filed Apr. 10, 1990, now abandoned, whichis a continuation-in-part of U.S. patent application Ser. No. 07/403,277of M. Bodman et al filed Aug. 31, 1989, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention pertains to a method preparing substituted andunsubstituted N-hydroxy-2-aminobutane diacid derivatives which can bedehydrated to 2-aminobut-2-ene dioic acid derivatives, whichsubsequently can be converted to pyridine and quinoline derivatives.Unsubstituted hydroxylamines are reacted with substituted orunsubstituted unsaturated diacid derivatives to produceN-hydroxyaspartic acid derivatives which can be dehydrated to2-aminobut-2-ene dioic acid derivatives, which can subsequently bereacted with α,β-unsaturated carbonyl compounds to produce pyridinederivatives. When the hydroxylamine is substituted, with a phenyl group,for example, so that N-phenyl-N-hydroxy-2-aminobutane dicarboxylic acidderivative is produced, this derivative can be dehydrated to form2-anilinobut-2-ene dicarboxylic acid derivative which can furtherreacted with a Vilsmeier reagent such as an immonium salt to producequinoline derivatives.

2. Background Art

N-hydroxyamino acids are valuable precursors for natural amino acids,peptides, herbicides, antibiotics, growth promoting agents, antitumoragents, antifungal agents, and polymers. It has been known that theaddition of hydroxylamine to an unsaturated monocarboxylic acidderivative can be used to obtain N-hydroxyamino mono carboxylic acidderivative. However, addition of hydroxylmine to an unsaturateddicarboxylic acid, such as fumaric acid, in the presence of an enzymedoes not successfully result in the isolation of N-hydroxyaspartic acid,as reported in "Progress in the Chemistry of Organic Natural Products",L. F. Alves et al., Springer-Verlag (1988), page 230. Indeed, theutilization of enzyme extracts, such as Bacillus caderas or Proteusvulgaris also does not yield success in isolating this desired product,but resort must be made, through utilization of a benzyl group, toprotect the hydroxylamine moiety as reported by Kolasa, Can. J. Chem.,Vol. 63, 2139 (1985). Such methods are cumbersome and involve theremoval of protecting groups rather than employing hydroxylamine or asalt thereof directly.

K. Bashceruddin et al., Synthetic Communications, 9, 705-712 (1979)reports the questionable result of obtaining of N-hydroxyaspartic acidsof greatly different melting points from maleic acid and fumaric acid,utilizing hydroxylamine. The reaction conditions for such conversion(s)are not disclosed, nor is revealed the criticality involved forobtaining N-hydroxyaspartic acid or its derivatives, namely a criticalpH. Furthermore, the only relevant reaction conditions revealed in thispublication, those for preparation ofN-hydroxy-3-amino-3-(p-nitrophenyl)propionic acid from p-nitrocinnamicacid, do not yield N-hydroxyaspartic acid.

Literature methods for preparing 5,6-dialkyl and5-alkyl-6-arylpyfidine-2,-3-dicarboxylic acids and esters are limitedand often require oxidation of alkyl or aryl substituents at positions 2and 3 in order to obtain diacids. Recently there has been disclosed amethod for the preparation of substituted and disubstitutedpyridine-2,3-dicarboxylic acid esters and 2-alkylnicotinates utilizingα-halo-β-ketoesters and α,β-unsaturated aldehydes or ketones in thepresence of an ammonium salt. The use of α-halo-β-ketoesters is notdesired due to the fact that such materials are usually costly andunstable.

U.S. Pat. No. 4,723,011 discloses preparation of substituted anddisubstituted pyridine-2,3-dicarboxylates by the reaction of anα-halo-β-ketoester such as chloro-diethyloxaloacetate (chloro-DOX) andan α, β-unsaturated aldehyde or ketone such as 2-ethylacrolein in thepresence of at least 2 molar equivalents of an ammonium salt in order toproduce the desired compounds.

U.S. Pat. No. 4,816,588 discloses and claims a process for preparingpyridine-2,3-dicarboxylic acids by the oxidation of 8-substitutedquinolines.

European Patent Application No. 274,379 published Jul. 13, 1988discloses two processes for producing pyridine-2,3-dicarboxylic acidcompounds. One process seems similar to that previously described inU.S. Pat. No. 4,723,011 and the other process involves reacting anα,β-unsaturated aldehyde or ketone with various aminomaleates oraminofumarates such as diethyl aminomaleate.

European Patent Application No. 299,362 published Jan. 18, 1989 alsodiscloses the same reaction.

U.S. Pat. No. 4,675,432 to Donald R. Maulding, issued Jun. 23, 1987describes a method for the preparation of anilinofumarate. Adichlorosuccinate is reacted with a molar equivalent of aniline in aninert organic solvent and with two or more molar equivalents of anaqueous base in the presence of a phase transfer catalyst to produce theanilinofumerate.

U.S. Pat. No. 4,656,283 to Robert F. Doehner, Jr., issued Apr. 7, 1987describes a method for the preparation of alkyl esters of substituted2-methyl-quinoline-3-carboxylic acid and quinoline-2,3-dicarboxylic acidas well as dialkyl 3-(substituted)-phenylaminobut-2-ene-dioates. Anappropriately substituted aniline is reacted with approximately anequimolar amount of a keto-ester to produce the productsabove-described.

Although the methods described above are useful for producing some ofthe reaction products produced by the method of the present invention;due to the broad utility of the reaction products of the presentinvention, as nutrient supplements, and as intermediaries in theproduction of pharmaceuticals, dyes and pigments and herbicides, anyimprovement in the method of production is of tremendous potentialeconomic significance.

SUMMARY OF THE INVENTION

The present invention pertains to a method of preparing substituted andunsubstituted N-hydroxy-2-aminobutane diacid derivatives which can bedehydrated to 2-aminobut-2-ene dioic acid derivatives, whichsubsequently can be converted to pyridine and quinoline derivatives. Anunsubstituted hydroxylamine is reacted with an substituted orunsubstituted unsaturated diacid derivative to produce N-hydroxyasparticacid derivatives which can be dehydrated to 2-aminobut-2-ene dioic acidderivatives, which can subsequently be reacted with α,β-unsaturatedcarbonyl compounds to produce pyridine derivatives. In the alternative,a single pot reaction can be carried out wherein the unsubstitutedhydroxyl amine is contacted with a substituted or unsubstitutedunsaturated diacid derivative, followed by a dehydration technique, withsubsequent addition of the α,β-unsaturated carbonyl compound, to producethe pyridine derivative directly (without isolation of the2-aminobut-2-ene dioic acid derivative formed upon the dehydrationstep).

In addition, when the hydroxylamine is substituted with a phenyl groupso that N-phenyl-N hydroxy-2-aminobutane dicarboxylic acid is produced,this derivative can be dehydrated to produce substituted andunsubstituted 2-anilinobut-2-ene dicarboxylic acid derivative which canbe further reacted with a Vilsmeier reagent to produce quinolinederivatives.

The chemical formulae representing the above-described method are shownbelow:

I. Synthesis of N-Hydroxy-2-aminobutane Diacid Derivatives

In accordance with the present invention, in preparation of thesubstituted and unsubstituted N-hydroxy-2-aminobutane diacidderivatives, it was discovered that the pH of the reaction medium iscritical, and should range from about 5 to about 12 and preferably fromabout 6.5 to about 9. In addition, the present invention permitsreaction at ambient temperatures (about 25° C.) to about 80° C., wherebyreaction products which tend to be thermally unstable at highertemperatures are preserved.

The reaction is represented by the following formulae: ##STR1## wherein:R═H, alkyl (preferably C₁ -C₆ straight or branched), substituted orunsubstituted aryl (preferably phenyl or naphthyl), and wherein thesubstituents are selected from alkyl, alkoxy, carboxy, halogen, cyano,and nitro;

R₁ and R₂ =each independently, ##STR2## wherein Z is OR₅ or NR₅ R₆ ; orCN; or

R₁ and R₂ together is ##STR3##

R₃ and R₄ are each independently H; alkyl; halogen; CN; substituted andunsubstituted aryl (preferably phenyl and naphthyl) wherein thesubstituents are selected from alkyl, arylalkyl, alkoxy, carboxy,halogen, nitro, and cyano; ##STR4## wherein Z is defined as above;

R₅ and R₆ are each independently H, alkyl (preferably C₁ -C₆ straight orbranched), aryl (preferably phenyl), arylalkyl (preferably aryl C₁ -C₆alkyl); or

R₅ and R₆ together with the nitrogen atom form a heterocyclicsubstituent, selected from pyrrolidinyl, piperidinyl, imidazolidyl,hydrogenated pyrimidinyl, including dihydro-, tetrahydro-, andhexahydropyrimidinyl; and

R₇ is H, alkyl (preferably C₁ -C₆ straight or branched), substituted orunsubstituted aryl (preferably phenyl), or an alkoxy of 1-6 carbonatoms.

II. Conversion of the N-Hydroxy-2-aminobutane Diacid Derivative to a2-Aminobut-2-ene Dioic Acid Derivative with Subsequent Conversion toNitrogen-Comprising Aromatic Compounds

Compounds I-D are used in a second embodiment of this invention, whereinCompounds I-D are subjected to dehydration to produce 2-aminobut-2-enedioic acid derivatives, Collective Compound II.

Compound II-A, Compound II-B or the tautomer Compound II-C which havethe formulae ##STR5## respectively, wherein R is as described above andwherein R' is R1, R" is R2, and R'" is R4, or R' is R2, R" is R1, andR'" is R3 including all the geometric isomers of Compounds IIA and lIB,including the compounds ##STR6## (Compounds II-A, II-B, II-C and thegeometric isomers of Compounds II-A and II-B are hereinaftercollectively referred to as Collective Compound II).

In another embodiment of the present invention, Collective Compound II,when R is H and R₃ and R₄ are H or halogen, can be reacted withα,β-unsaturated carbonyl compounds of the formula II-D ##STR7## whereinR₈ and R₁₀ =H, alkyl or alkenyl (preferably C₁ -C₆ straight or branched)or substituted or unsubstituted aryl (preferably phenyl or naphthyl),wherein the substituents are selected from alkyl, alkoxy, carboxy,carboalkoxy, halogen, and cyano;

wherein R₉ =the same as R₈ and R₁₀, but also including halogen, andwherein R₉ and R₁₀ taken together can be --(CH₂)--₃₋₁₀ ; to producepyridine derivative of the Formula II-E ##STR8## wherein R₈, R₉, and R₁₀are as described above. Particular embodiments of the conversion ofspecific compounds included in Collective Compounds II to specificcompounds included in Compound II-E, wherein R₈, R₉, and R₁₀substituents are as revealed and defined as corresponding substituentsR₁, R₂, R₃, and R₆ of U.S. Pat. No. 4,758,667, incorporated by referencehereinto in its entirety.

Compound II-E, in turn, is a precursor in the synthesis of Compound II-Fof the formula ##STR9## wherein R₁₁ and R₁₂ are each independently ofthe other C₁ -C₆ alkyl, as revealed and defined as corresponding tosubstituents R₄ and R₅ in U.S. Pat. No. 4,758,667, incorporated hereintoby reference. Compound II-F has herbicidal properties and can be usedfor controlling undesired plant growth.

Throughout the specification and appended claims, a given chemicalformula or name shall encompass all geometric, optical isomers andracemic mixtures thereof where such isomers exist.

In the above definitions, the term "aryl" refers to a monovalentsubstituent which consists of an aryl group, e.g. phenyl, o-toluyl,m-methoxyphenyl, etc., of the formula ##STR10## where X is hydrogen,halogen, lower alkyl, lower alkoxy, CF₃, and NO₂ and n is an integer of1 to 5; the term "arylalkyl" refers to a monovalent substituent whichconsists of an aryl group, e.g. phenyl, o-toluyl, m-methoxyphenyl, etc.,linked through an alkylene group having its free valence bond from acarbon of the lower alkylene group, and having a formula of ##STR11##where X and n are is as defined above; the term "alkylene" refers to abivalent radical of the lower branched or unbranched alkyl group it isderived from having valence bonds from two terminal carbons thereof,e.g. ethylene (--CH₂ CH₂ --), propylene (--CH₂ CH₂ CH₂ --), ##STR12##etc; the term "alkoxy" refers to a monovalent substituent which consistsof an alkyl group linked through an ether oxygen having its free valencebond from the ether oxygen, e.g. methoxy, ethoxy, propoxy, butoxy,pentoxy, etc.

In the alternative:

III. Single Pot Formation of the Pyridine Derivative from Substituted orUnsubstituted Diacid Derivatives, Unsubstituted Hydroxylamine, and α,β-Unsubstituted Carbonyl Compounds. ##STR13## wherein: R═H;

R₁ and R₂ =each independently H, alkyl (preferably C₁ -C₆ straight orbranched), aryl (preferably substituted or unsubstituted phenyl ornaphthyl), COZ, or CN, provided both are not H, and wherein Z=OR₅ or NR₅R₆, wherein R₅ and R₆ are as described above; or R₁ and R₂ are together--CO--NR₁ --CO, wherein R₁ is as described above. R₃ and R₄ ofCollective Compound II=H, or halogen; R₈ and R₉ are as described above;

R₉ and R₈ and R₉ taken together are as described above.

The expression substituted-aryl preferably is intended to mean phenyl ornaphthyl substituted in one or more positions with halogen (bromine,chlorine, fluorine or iodine); C₁ -C₆ alkyl; alkoxy of 1-6 carbon atoms,cyano, nitro, or carboxy.

The α,β-unsaturated carbonyl compounds are preferably aldehyde or ketonewherein R₈, R₉, and R₁₀ are as described above.

The acetal and ketal derivatives of the carbonyl compounds, or theMannich base equivalent to such carbonyl compounds can also be used inthe invention.

IV. Preparation of Quinoline Derivatives by Reacting a Substituted orUnsubstituted Phenylhydroxyamine with a Substituted or UnsubstitutedUnsaturated Diacid Derivative to Form a Phenylhydroxylamine Adduct,Dehydrating to Form Substituted and Unsubstituted 2-Anilino-But-2-EneDicarboxylic Acid Derivative, Followed by Reaction with VilsmeierReagent to Form a Quinoline Derivative ##STR14## wherein R₁, R₂, R₃, andR₄ as descried in Section III above; wherein R₁₃ is H, alkyl (preferablyC₁ -C₆ straight or branched, aryl (preferably phenyl or naphthyl),alkoxy, halogen, cyano, carboalkoxy, thioalkoxy, or CF₃. DETAILEDDESCRIPTION

More specifically, the preferred embodiments of the above-describedmethod follow. Throughout the specification and appended claims, a givenchemical formula or name shall encompass all geometric, optical isomersand racemic mixtures thereof where such isomers exist.

I. Synthesis of N-Hydroxy-2-aminobutane Dicarboxylic Acid Derivatives

The present invention is described in terms of synthesizing esters ofN-hydroxyaspartic acid and esters of 2-aminobut-2-ene dioic acids, suchas dialkyl 2-aminomaleate. However, it should be understood that suchdescription is exemplary only and is for purposes of exposition and notfor purposes of limitation. It will be readily appreciated that theinventive concept described is equally applicable to both substitutedand unsubstituted N-hydroxyaspartates as well as esters which are alkylor aryl.

This embodiment of the present invention relates to a method ofsynthesizing a N-hydroxyaspartic acid derivative of the formula:##STR15## where R₁ and R₂ are each independently ##STR16## where Z isOR₅ or NR₅ R₆ where R₅ and R₆ are each independently H, alkyl(preferably C₁ -C₆ alkyl branched or straight), aryl (preferably phenylor naphthyl), arylalkyl, or R₅ and R₆ together with the nitrogen atomform a heterocyclic substituent, selected from pyrrolidinyl,piperidinyl, imidazolidyl, hydrogenated pyrimidinyl, including dihydro-,tetrahydro-, and hexahydropyfimidinyl; CN, or R₁ and R₃ together is##STR17## where R₇ is as defined above; and R₃ and R₄ are eachindependently H, alkyl (preferably C₁ -C₆ alkyl branched or straight),aryl (preferably phenyl or naphthyl), arylalkyl, ##STR18## where Z is asdefined above; CN, and halogen.

The term "alkyl" refers to a straight or branched chain hydrocarbon of 1to 18 carbon atoms containing no unsaturation, e.g. methyl, ethyl,isopropyl, 2-butyl, neopentyl, n-hexyl, n-heptyl, n-nonyl, etc.; theterm "aryl" refers to a monovalent substituent which consists of an arylgroup, e.g. phenyl, o-toluyl, m-methoxyphenyl, etc., of the formula##STR19## where X is hydrogen, halogen, lower alkyl, lower alkoxy, CF₃,and NO₂, and n is an integer of 1 to 5; the term "arylalkyl" refers to amonovaient substituent which consists of an aryl group, e.g. phenyl,o-toluyl, m-methoxyphenyl, etc., linked through an alkylene group havingits free valence bond from a carbon of the lower alkylene group, andhaving a formula of ##STR20## where X and n are is as defined above; theterm "alkylene" refers to a bivalent radical of the lower branched orunbranched alkyl group it is derived from having valence bonds from twoterminal carbons thereof, e.g. ethylene (--CH₂ CH₂ --), propylene (--CH₂CH₂ CH₂ --), isopropylene , etc; the term "alkoxy" refers to amonovalent substituent which consists of an alkyl group linked throughan ether oxygen having its free valence bond from the ether oxygen, e.g.methoxy, ethoxy, propoxy, butoxy, pentoxy, etc.

The synthesis of N-hydroxyaspartic acid derivative (Compound I-D, when Ris H) is made in the following manner. The substituents R₁, R₂, R₃, R₄,R₅, R₆, and Z are as defined above unless indicated otherwise.

A suitable diacid derivative of the formula ##STR21## is selected. Suchdiacid derivatives are well known or can be synthesized usingconventional techniques well known to those of ordinary skill in theart. Compound I-B or I-C is reacted with substituted hydroxylamineR--NH--OH or with unsubstituted hydroxylmine, H--NH--OH, or a suitablesalt thereof, to produce N-hydroxyaspartic acid derivative. For purposesof simplification, subsequent descriptions will be limited tounsubstituted hydroxylamine, although it is understood the hydroxylaminecan be substituted as well. A suitable hydroxylmine salt includes amineral acid salt such as hydroxylamine hydrochloride, hydroxylaminesulfate, hydroxylamine bisulfate, hydroxylamine phosphate etc. or anorganic acid salt, e.g. hydroxylamine acetate, etc. The reaction may becarded out with or without a suitable solvent. If carded out in asolvent, a suitable solvent includes water, a lower alkanol, e.g.methanol, ethanol, isopropanol, 1-butanol, etc.; a halogenated lowerhydrocarbon or alkane e.g. dichloromethane, chloroform,carbontetrachloride, dichloromethane etc.; an aromatic hydrocarbon, e.g.benzene, toluene, etc.; an ether, e.g. ethylether, dioxane,tetrahydrofuran, etc.; an ester, e.g. ethyl acetate, isopropyl acetate,butyl acetate, etc.; and an aprotic solvent, e.g. acetonitrile,dimethylformamide, dimethylsulfoxide, etc; and mixtures thereof.

It is critical that the reaction be conducted under weakly acidic tobasic conditions (pH=5-12) since it has been found that when thecorresponding dicarboxylic acid of Compound I-B or I-C is employed, e.g.maleic acid or fumaric acid, addition of the hydroxylamine across thedouble bond leading to the N-hydroxyaspartic acid does not occur.Additionally, where the reaction between Compound I-B or I-C and thehydroxylamine or its salt is conducted under more acidic pH conditions,the desired reaction again does not occur to yield the N-hydroxyasparticacid derivative. The reaction must be carried out under critical pHconditions which are at most weakly acidic, i.e. the upper acid pH rangebeing weakly acid, that is, at a pH region of 5 through about 12,preferably a pH range of about 6.5 to about 9.

During the reaction of hydroxylamine with Compound I-B or I-C, thehydroxylamine itself provides the basic medium. When a hydroxylaminesalt is used, a suitable base should be employed to achieve the criticalpH reaction condition. A suitable base is one selected from an inorganicbase, e.g. sodium hydroxide, potassium hydroxide, ammonium hydroxide,sodium carbonate, potassium carbonate etc.; an organic base, e.g.pyridine, triethylamine, sodium methoxide, etc., present in an amountranging from about 1 to about 3 moles of base to one mole ofhydroxylamine salt, and preferably from 1 mole of base per one mole ofhydroxylamine salt, except in the case of a hydroxylamine salt of adiprotic acid, such as hydroxylamine sulfate, wherein 2 moles of baseper mole of salt is preferred.

It is to be understood that pH values, resulting when there are solventlevelling effects involved, which correspond to the above-identifiedcritical pH range are equally applicable.

Compound I-B or I-C and the hydroxylamine or its salt, are employed in amole ratio ranging from about 1:1 to about 1:3, with the preferred moleratio being between 1:1 to 1:1.5 of Compound I-B or I-C to thehydroxylamine or its salt.

Typically the reaction, conducted with the mole ratios of Compound I-Bor I-C, hydroxylamine or its salt, and base, as indicated above, iscarried out at a temperature ranging between about -10° C. to about 80°C., preferably about 10° C. to about 50° C., for a time period rangingfrom about 0.1 to about 15 hours to obtain addition of the NH₂ OH (orRNHOH) across the carbon-carbon double bond of Compound I-B or I-C,typically following Markovnikov's rule, to obtain Compound I-E (orCompound I-D). ##STR22## Compound I-E includes, but is not limited to,dimethyl N-hydroxyaspartate, diethyl N-hydroxyaspartate, dipropylN-hydroxyaspartate, di-iso-propyl N-hydroxyaspartate, di-n-butylN-hydroxyaspartate, N-hydroxyaspartonitrile and triethyl2-(N-hydroxyamino)-ethanetricarboxylate.

If Compound I-D is an ester, of course it can be hydrolyzed, usingconventional techniques, to obtain the free acid, i.e. ##STR23## Theexamples which follow are for purposes of illustrating the embodiment ofthe present method described under I above, and are not to be construedas limiting the invention disclosed herein.

Example 1 Diethyl N-Hydroxyaspartate

Hydroxylamine free base (50% aqueous solution, 45.0 g, 0.68 mol) wasadded dropwise to diethyl maleate (100.0 g, 0.56 mol) under nitrogen.The reaction temperature was maintained below 55° C. with an ice bath.The mixture was stirred for 30 minutes. Dichloromethane (100 ml) wasadded to the reaction mixture and the organic layer was collected. Theorganic layer was concentrated under reduced pressure to give crudediethyl N-hydroxyaspartate (103 g, 89% yield). The product was analyzedby NMR spectroscopy and found to be greater than 95% pure.

Example 2 Diethyl N-Hydroxyaspartate

Sodium hydroxide (40% aqueous solution, 12.9 g, 0.129 mol) was addedover 20 minutes to a stirred mixture of diethyl maleate (17.3 g, 0.1mol) and hydroxylamine sulfate (25% aqueous, 39.0 g, 0.059 mol) duringwhich the reaction temperature rose from 28° C. to 53° C. The reactionmixture was stirred for 30 minutes under nitrogen. The mixture wastransferred to separating funnel, methylene chloride was added (50 ml),the organic layer was collected and concentrated to give diethylN-hydroxyaspartate (18.5 g, 0.99 mol, 90% yield).

Example 3 Diethyl N-Hydroxyaspartate

Sodium hydroxide solution (50% aqueous, 96.0 g, 1.2 mol) was added over30 minutes to an aqueous solution of hydroxylamine sulfate (25%, 394.2g, 0.6 mol). The temperature was kept below 40° C. during the causticaddition. The reaction pH was about 9 at the end of caustic addition.

Diethyl maleate (172.0 g, 1.0 mol) was then added to the reaction andstirred for 60 minutes at which time the pH was about 7.4. The reactionmixture was transferred to a separatory funnel, the layers were allowedto separate, and the organic phase containing diethyl N-hydroxyaspartatewas separated. The crude product was analyzed by NMR and found tobe >90% pure (207 g).

Example 4 Preparation of Diethyl N-hydroxyaspartate

Hydroxylamine Free base (50% aq. soln., 45.0 g, 0.68 mol) was addeddropwise to a solution of diethyl maleate (100.0 g, 0.56 mol) in ethanol(100 mL) in a 3-neck flask blanketed with nitrogen. The reactiontemperature was maintained below 55° C. with an ice bath. The mixturewas stirred for 30 minutes. The reaction mixture was concentrated underreduced pressure to give crude diethyl N-hydroxyaspartate (103 g, 89%yield). The product was analyzed by nuclear magnetic resonancespectroscopy (NMR) and shown to be at least 95% pure. NMR (acetone-d6)1.20 (m, 6H), 2.59 (dd, J 6.8, 16.1 Hz, 1H), 2.76 (dd, J 6.8, 16.1 Hz,1H), 3.89 (t, J 6.8 Hz, 1H), and 4.11 (m, 4H).

Example 5 Dimethyl N-Hydroxyaspartate

Hydroxylamine free base (50% aqueous solution, 7.3 g, 0.11 mol) wasadded over a 30 minute period to dimethyl maleate (15.0 g, 0.1 mol)under nitrogen. The reaction temperature was maintained below 55° C.with an ice bath. The mixture was stirred for 30 minutes. The reactionmixture was added to dichloromethane (200 ml) and the organic phase wasseparated. The organic phase was dried with magnesium sulfate andconcentrated to give dimethyl N-hydroxyasparate (16.2 g, 90% yield).

Example 6 Dibutyl N-Hydroxyaspartate

Hydroxylamine free base (50% aqueous solution, 8.0 g, 0.12 mol) wasadded dropwise to dibutyl maleate (25.0 g, 0.1 mol) in a 3-neck 250 mlflask blanketed with nitrogen. The reaction temperature was maintainedbelow 55° C. with an ice bath. The mixture was stirred for 30 minutes.The gas liquid chromatography (GLC) analysis of the reaction mixtureindicated 96% conversion of dibutyl maleate. The NMR analysis showedthat the reaction mixture contained dibutyl N-hydroxyaspartate ingreater than 95% purity.

Example 7 N-Hydroxyaspartonitrile

Hydroxylamine free base (50% aqueous solution, 2.0 g, 30.3 mmol) wasadded over 2 minutes to a suspension of fumaronitrile (2.0 g, 25.6 mmol)in ethanol (15.0 g). During the course of the hydroxylamine addition,the reaction temperature changed from 18° C. to 48° C. The reactionmixture was cooled to room temperature and stirred for one hour. The GLCanalysis of the reaction mixture showed that the reaction proceeded withcomplete conversion of fumaronitrile to give N-hydroxyaspartonitrile in90% selectivity. The solvent was removed and the product wascharacterized by NMR.

Example 8 Triethyl 2-(N-hydroxyamino)-1,1,2-ethanetricarboxylate orDiethyl 3-(Carboethoxy)-N-hydroxyaspartate

Triethyl ethenetricarboxylate (4.0 g, 16.3 mmol), obtained from diethylmalonate and ethyl glyoxalate, was dissolved in ethanol (25 g) andhydroxylamine (50% aqueous solution, 1.3 g, 19.6 mmol) was added to thereaction mixture. A solid precipitated out within 10 minutes indicatingthe completion of the reaction. The solvent was removed under reducedpressure to give the crude product. The crude product was analyzed byNMR and found to have triethyl 2-(N-hydroxyamino)ethanetricarboxylate.

II. Conversion of the N-Hydroxy-2-Aminobutane Diacid Derivative to a2-Aminobut-2-ene Dioic Acid Derivative with Subsequent Conversion toNitrogen-Comprising Aromatic Compounds

Compound I-D, where at least either R₃ or R₄ is hydrogen can then besubjected to dehydration using conventional techniques well known tothose skilled in the art to obtain a 2-aminobut-2-ene dioic acidderivative (Collective Compound II). The dehydration of Compound I-D canbe affected by heating. This dehydration by heating can be conductedwith or without a suitable dehydration agent. If a dehydration agent isemployed, the agent is typically present in an amount ranging from about0.1% to about 100% by weight, preferably about 0.1% to about 10% byweight, to yield the 2-aminobut-2-ene dioic acid derivative.

Any dehydration agent known in the art can be employed. Some suitabledehydration agents include an inorganic acid catalyst, e.g. H₂ SO₄, HCl,phosphoric acid, polyphosphoric acid, etc.; an ion exchange acidicresin, e.g. Amberlyst®, Dowex®, NationoH®, etc.; an organic acid, e.g.p-toluenesulfonic acid, methanesulfonic acid, etc.; an inorganic base,e.g. potassium bicarbonate, sodium carbonate, etc.; an organic base,e.g. pyridine, triethylamine, etc.; a basic ion exchange resin, e.g.Amberlyst®, Dowex®, etc., or a transition metal catalyst, e.g.palladium, rhodium, etc.

Dehydration can also be carded out using acylation agents or acombination of acylation agent and an organic base of the kind describedabove. The acylation agents include carboxylic acid anhydride, e.g.acetic anhydride and trifluoroacetic anhydride; and acid chloride, e.g.acetyl chloride and propanoyl chloride.

Typically the dehydration, with or without suitable agent, can be cardedout in a suitable solvent, e.g. water, alcohols, such as ethanol,butanol, hydrocarbons, such as heptane, parafins; halogenatedhydrocarbons such as chloroform and methylene chloride; aromatichydrocarbons such as toluene, xylene; ethers, polar aprotic solventssuch as dimethylformamide, diglyme, tetraglyme, etc., at a temperatureranging from about 25° C. to about 300° C., preferably about 50° C. toabout 200° C., for about 0.01 to about 48 hours, to obtain2-aminobut-2-ene dioic acid.

Compound I-D is then dehydrated using heat and/or a dehydration agent,as shown under Section II, above to form Collective Compounds II whichare subsequently reacted with an α,β-unsaturated carbonyl compound suchas an aldehyde or ketone (Compound II-D).

The resultant Collective Compound II, represented in part by thecompounds of the formulae as previously described on Pages 7 and 8##STR24## can be isolated. When R is H and when at least R₃ is hydrogenor halogen, then Collective Compound II can be reacted with asubstituted α,β-unsaturated carbonyl compound of the formula ##STR25##where R₈, R₉, and R₁₀ are as defined above (and which correspond to R₁,R₂ and R₃, respectively, of U.S. Pat. No. 4,758,667), to obtain acompound of the formula ##STR26## which includes2,3-pyridinedicarboxylic acid derivatives such as5-alkylpyridine-2,3-dicarboxylic acid.

The reaction between Collective Compounds II and those of Formula II-Dis conveniently carried out by heating the same in the presence of anacid and suitable solvent preferably at reflux for periods of timeranging from 0.5 to 48 hours. Although the preferred temperature is atreflux, any temperature from ambient up to the boiling point of thesolvent can be employed. A relative pH between 3-4 appears optimalalthough a pH ranging from 2-7 can be used.

The mole ratio of the compounds of Formula I-D to the aldehydes orketones of Formula II-D is not critical and can range from about 1:3 to3:1. It is preferred to use approximately from 1:1.0 to 1:1.3 molarratios.

If desired a dehydrogenation catalyst can be added to the reactionmixture of Collective Compounds II and II-D, in order to aid inaromatization of the newly-generated ting. The dehydrogenation catalystwhen employed is conventional in the art and includes metals orcompounds of platinum, palladium, ruthenium, ifidium, nickel, iron,copper, cobalt, rhodium, etc. The dehydrogenation metal or compoundthereof deposited on a suitable support, such as alumina, carbon, clay,zeolites, chromia, zirconia, etc. A preferred dehydrogenation catalystis palladium on carbon.

As has been previously stated, an acid is employed to provide an acidicpH range (from about 2 to about 7). Suitable acids include inorganicacids such as hydrochloric, phosphoric, sulfufic, etc. and preferablyorganic acids such as acetic, trifiuoroacetic, p-toluenesulfonic,methanesulfonic, trifluoromethanesulfonic, propionic, butyric or othercarboxylic acids including aromatic carboxylic acids. Ion-exchangeresins such as Amberlyst®, Dowex®, NAHON® can also be used as acidiccomponents.

When an acid is used which is also a solvent i.e. acetic acid, noadditional solvent is required.

Solvents suitable for use during the reaction of Collective Compounds IIwith Compounds II-D include: water, alcohols, chlorinated hydrocarbons,hydrocarbons, aromatic hydrocarbons, ethers, organic acids, esters, andaprotic solvents such as acetonitrile. The preferred solvents are loweralkyl alcohols, such as methanol, ethanol, propanol, and butanol andaromatic hydrocarbons, such as benzene and toluene. Particularlypreferred solvents are 1-butanol and/or ethanol.

Thus, pyridinecarboxylic acid derivatives containing substituents in the4-,5- and 6- position may conveniently be prepared by dehydratingFormula I-D N-hydroxyamino derivatives to form at least one of theCollective Compound II compounds which is then admixed with a FormulaII-D α,β-unsaturated aldehyde or ketone in the presence of an acid andpreferably a solvent, and stirring the resulting reaction mixture at atemperature in the range of ambient temperature to the boiling point ofthe solvent, and preferably at reflux, until the reaction is essentiallycomplete and isolating the formed 4-substituted, 4-5-disubstituted,4,6-disubstituted, 5-substituted, 6-substituted or 5,6-disubstitutedpyridine-2,3-dicarboxylic acid derivatives by standard laboratorytechniques such as extraction, evaporation, distillation or columnchromatography.

Compound II-E, which includes 2,3-pyridine carboxylic acid derivatives,can be reacted with a 2-aminoalkane carboxamide, as defined in U.S. Pat.No. 4,758,667, and reacted as described in this patent to form the2-(imidazolin-2-yl)-3-pyridine carboxylic acids described therein.

The examples which follow are for purposes of illustrating theembodiment of the present method described under II above, and are notto be construed as limiting the invention disclosed herein.

Example 9 Diethyl 3-Aminomaleate by Thermolysis

A solution (10 ml) of diethyl N-hydroxyaspartate (9.4% solution, 7.8 g,3.6 mmol) in ethanol was fed in a quartz column (1 inch ID) containingglass beads (3 inches long) at 200° C. at the rate of 0.2 ml per minutealong with nitrogen at a rate of 1000 ml per minute. The vaporizedmaterial escaping at the end of quartz column was collected using adry-ice trap. The condensate (0.35 g) was analyzed by GLC. The analysisfound that the reaction gave diethyl 2-aminomaleate in about 34.5%yield.

Example 10 Diethy12-Aminomaleate using an Acid Dehydration Agent

Hydroxylamine free base (50% aqueous solution, 2.0 g, 30.3 mmol) wasdropwise added to diethyl maleate (4.41 g, 25.6 mmol) and stirred for 60minutes at 40°-45° C. to give diethyl N-hydroxyaspartate. Toluene (5.02g) and p-toluenesulfonic acid (0.05 g, 0.26 mmol) were added to thereaction mixture and refluxed for 4.5 hours. The reaction mixture wasanalyzed by GLC, which showed that the reaction proceeded to give 89%diethyl 2-aminomaleate (80% yield based on the external standard).

Example 11 Preparation of Diethyl 2-aminomaleate Using Acetic Anhydride

Triethylamine (6.5 g, 64.4 mmol) was added dropwise to diethylN-hydroxyaspartate (11.95 g, 58.3 mmol) and stirred at room temperaturefor 15 minutes. Acetic anhydride (6.58 g, 64.5 mmol) was then addeddropwise to the reaction mixture while temperature was maintained below40° C. using an ice bath. The reaction was stirred at room temperaturefor an hour and at 60°-70° C. for another hour. The reaction wasanalyzed by GLC. The analysis found the reaction mixture to containmainly diethyl 2-aminomaleate with about 10% of diethylN-acetyl-2-aminomaleate.

Example 12 Diethyl 2-Aminomaleate and Diethyl 2-Iminosuccinate

Hydroxylamine (50% aqueous solution, 2.05 g, 31.1 mmol) was added to asolution of diethyl maleate (4.3 g, 25.0 mmol) in ethanol (10 ml) atroom temperature. The reaction mixture temperature increased to 70° C.within five minutes. The reaction mixture was cooled to room temperatureand stirred for 48 hours. The GLC analysis showed that the reactionmixture contained 33% diethyl N-hydroxyaspartate, 32% diethyl2-aminomaleate, and 21% diethyl 2-iminosuccinate.

Example 13 Aminomaleate Conversion to 5-Ethylpyridine-2,3-Dicarboxylate

Acetic acid (10 ml) was added to a solution of diethyl 2-aminomaleate(18.7 g, 0.10 mol) in ethanol (38 ml) in a 250 ml flask. The reaction pHwas measured and found to be 3.9. The reaction flask was equipped with areflux condenser, thermometer, heating mantle, stirrer, and droppingfunnels. Then, 2-ethylacrolein (12.8 g, 0.13 mol) was added all at onceand the reaction mixture was heated to reflux for 3 to 5 hours. Thesolvent was removed on a vacuum rotary evaporator and the residue wasvacuum distilled. The yield of diethyl 5-ethylpyridine-2,3dicarboxylatewas 13.8 g (55% of theoretical).

Example 14 Aminomaleate Conversion to 5-Methylpyridine-2,3-Dicarboxylate

Repeating the process described in Example 13 with 2-methylacrolein(10.9 g, 0.13 mol) gave 9.0 g (38% yield) of diethyl5-methylpyridine-2,3-dicarboxylate.

III. Single Pot Formation of the Pyridine Derivative from Substituted orUnsubstituted Diacid Derivatives, Unsubstituted Hydroxylamine, andα,β-Unsaturated Carbonyl Compounds

Another embodiment of the invention involves the single-pot preparationof substituted and disubstituted pyridinecarboxylates of Formula II-E byreacting a diacid derivative of Formula I-B or I-C: ##STR27## wherein R₁and R₂ are defined above with unsubstituted hydroxylamine of Formula(I-A) or a salt thereof, such as the hydrochloride, salt at ambienttemperatures for periods of time ranging from about 30 minutes to about3 hours at a pH ranging from about 6 to about 12. The resulting reactionproduct is then subjected to dehydration using heat or a dehydratingagent, or both, at temperatures ranging from about 25° C. to about 200°C., for a time period ranging from about 1 second to about 12 hours.After dehydration, an acid is added to lower the pH to 2-7, orpreferably 3-4, and an α,β-unsaturated aldehyde or ketone of FormulaII-D is added, and the reaction mixture is subjected to elevatedtemperatures ranging from about 50° C. to about 125° C. for periods oftime ranging from about 1 to about 48 hours.

A preferred embodiment of the invention involves the preparation ofsubstituted and disubstituted pyridinedicarboxylates of Formula II-F bytreating a alkene of Formula I-B or I-C wherein R₁ and R₂ are definedabove with a substituted or unsubstituted hydroxylamine or a mixture ofa hydroxylamine salt and a base at a temperature of 15° C. to 60° C. forperiods of 0.1 to 2 hours at a pH of 7-9. The resulting reaction productis then subjected to dehydration using heat or a dehydrating agent, orboth, at temperatures ranging from about 25° C. to about 200° C., for atime period ranging from about 1 second to about 12 hours. Afterdehydration, sufficient acid to take the pH to 2-7, preferably 3-4, andpreferably a solvent, is added. Then an α,β-unsaturated aldehyde orketone of Formula II-D is added, and the resulting mixture is stirred ata temperature in the range of ambient temperature to the boiling pointof the solvent, until the reaction is essentially complete.

The reaction mixture is then cooled to ambient temperature of 20°-40° C.The product is concentrated under reduced pressure and can be purifiedby conventional techniques such as distillation, extraction,evaporation, or column chromatography.

If desired a dehydrogenation catalyst can be added to the reactionmixture.

The dehydrogenation catalyst when employed is conventional in the artand includes metals or compounds of platinum, palladium, ruthenium,iridium, nickel, iron, copper, antimony, cobalt, rhodium, etc. Thedehydrogenation metal or compound thereof deposited on a suitablesupport, such as alumina, carbon, clay, zeolites, chromia, zirconia,etc. A preferred dehydrogenation catalyst is palladium on carbon.

When an acid is used which is also a solvent i.e. acetic acid, noadditional solvent is required.

Solvents suitable for use in the method of this invention include:water, alcohols, chlorinated hydrocarbons, hydrocarbons, aromatichydrocarbons, ethers, organic acids, esters, and aprotic solvents suchas acetonitrile. The preferred solvents are lower alkyl alcohols, suchas methanol, ethanol propanol and butanol and aromatic hydrocarbons,such as benzene and toluene. The particularly preferred solvents are1-butanol, ethanol, or toluene.

In another embodient pyfidine-2,3-dicarboxylic acid derivativescontaining substituents in the 4-, 5- and 6-position may conveniently beprepared by reacting, at a neutral or slightly basic pH, a Formula I-Bor I-C maleate or fumarate with a substituted or unsubstitutedhydroxylamine or a salt thereof, then subjecting the reaction product todehydration using heat or a dehydrating agent or both, and subsequentlyadding followed by a Formula II-D α,β-unsaturated aldehyde, or ketone,at a pH of 2-7 with an acid and preferably a solvent, and stirring theresulting reaction mixture at a temperature in the range of ambienttemperature to the boiling point of the solvent, and preferably atreflux, until the reaction is essentially complete and isolating theformed 4-substituted, 4,5-disubstituted, 4,6-disubstituted,5-substituted, 6-substituted or 5-6-disubstitutedpyridine-2,3-dicarboxylic acid derivatives by standard laboratorytechniques such as extraction, evaporation column chromatography, ordistillation.

The amount of substituted or unsubstituted hydroxylamine or salt thereofused ranges from about 1 to about 1.5 mols of hydroxylamine per mol ofsaid maleate or fumarate. Preferred ranges are about 1.0-1.2 mols.

If a hydroxylamine salt is used, a base such as sodium hydroxide,potassium hydroxide or ammonium hydroxide, in an amount of 1 to 2 moles,preferably 1 to 1.2 moles per mole of said hydroxylamine salt is neededto liberate the hydroxylamine.

The dehydration can be affected by heating. This dehydration by heatingcan be conducted with or without a suitable dehydration agent. If aagent is employed, the agent is typically present in an amount rangingfrom about 0.1% to about 100% weight, preferably about 0.1% to about 10%by weight. Any dehydration agent known in the art can be employed. Somesuitable dehydration agent is included in Section II of thisapplication.

The mol ratio of the alkene of Formula I-B and I-C to the aldehyde orketone of Formula II-D is not narrowly critical and can range from about1:1 to about 1:3. It is preferred to use approximately 1:1.0 to 1:1.3molar ratios.

It is believed that the reaction of the I-B and I-C maleates with thesubstituted or unsubstituted hydroxylamine or salt thereof inherentlyproduces the N-hydroxyamino derivatives of Formula I-D, which upondehydration produces 2-aminobut-2-ene dioic acid derivatives.

One of the preferred embodiments of the present invention pertains tothe synthesis of 2,3-pyridine-dicarboxylic acid derivative of theformula: ##STR28## where R₈ is hydrogen or C₁ -C₆ alkyl; R₉ is hydrogen,halogen, C₁ -C₆ alkyl, C₁ -C₆ hydroxyalkyl, C₁ -C₆ alkoxy, phenyl orphenyl substituted --C₁ -C₆ alkyl, or phenyl or phenyl --C₁ -C₆ alkyl,each substituted by C₁ -C₆ alkyl, C₁ -C₆ alkoxy or halogen; R₉ ishydrogen, C₁ -C₆ alkyl, phenyl, phenyl --C₁ -C₆ alkyl, or phenyl orphenyl C₁ -C₆ alkyl each substituted by one C₁ -C₆ alkyl, C₁ -C₆ alkoxyor halogen; R₈ and R₉ together are 1,3-butadienylene which can besubstituted by halogen, C₁ -C₆ alkyl, C₁ -C₆ alkoxy, C₁ -C₆ haloalkyl,C₁ -C₆ alkylsulfonyl, nitro, cyano, phenyl, phenoxy, or phenyl orphenoxy, each substituted by one C₁ -C₆ alkyl, C₁ -C₆ alkyoxy orhalogen, and R₁₄ is C₁ -C₈ alkyl, phenyl or C₁ -C₆ phenyl alkyl; whereembodiments of the compound of the preceeding formula and R₈, R₉, andR₁₀ substituents are as revealed and defined as correspondingsubstituents R₁, R₂, R₃, and R₆ of U.S. Pat. No. 4,758,667, incorporatedby reference hereinto in its entirety.

Such compounds in turn are a precursor in the synthesis of compounds ofthe formula ##STR29## where R₁₁ and R₁₂ are each independently of theother C₁ -C₆ alkyl, as revealed and defined as corresponding tosubstituents R₄ and R₅ in U.S. Pat. No. 4,758,667, incorporated hereintoby reference. The latter compound has herbicidal properties and can beused for controlling undesired plant growth.

The reactions described under Section III above are illustrated by theExamples which follow:

Example 15 Procedure without Pd/C

Hydroxylamine free base (50% aqueous solution, 2.0 g, 30.3 mmol) isadded dropwise to diethyl maleate (4.41 g, 25.6 mmol) and stirred for 60minutes to give diethyl N-hydroxyaspartate. Toluene (25.02 g) andp-toluenesulfonic acid (0.05 g, 0.26 mmol) are added to the reactionmixture and refluxed for 4.5 hours to afford diethyl 2-aminomaleate. Thereaction mixture is cooled to room temperature and added acetic acid(7.0 g) and 2-ethylacrolein (2.13 g, 25, 0 mmol). The reaction mixtureis stirred at 80°-90° C. for 24 hours. It is concentrated under reducedpressure and analyzed by GLC using an external standard. The analysisshowed the yield of diethyl 5-ethylpyridine-2,3-dicarboxylate is about35%.

EXAMPLES 16-23

The procedure of Example 15 is repeated except that the following2-aminobut-2-ene dioic acid derivatives and aldehydes or ketones areused:

    ______________________________________                                        Aspartate          Aldehyde or Ketone                                         ______________________________________                                         ##STR30##                                                                                        ##STR31##                                                 ______________________________________                                                R.sub.15  R.sub.16                                                                              R.sub.9 R.sub.10                                                                            R.sub.8                               ______________________________________                                        Example 16                                                                            methyl    propyl  H       H     phenyl                                Example 17                                                                            propyl    propyl  phenyl  ethyl methyl                                Example 18                                                                            butyl     butyl   ethyl   methyl                                                                              H                                     Example 19                                                                            ethyl     ethyl   methyl  H     H                                     Example 20                                                                            ethyl     ethyl   H       methyl                                                                              H                                     Example 21                                                                            ethyl     ethyl   H       H     methyl                                Example 22                                                                            ethyl     ethyl   (CH.sub.2).sub.3                                                                          H                                       Example 23                                                                            ethyl     ethyl   (CH.sub.2).sub.4                                                                          H                                       ______________________________________                                    

IV. Preparation of Quinoline Derivatives by Reacting a Substituted orUnsubstituted Phenylhydroxyamine with a Substituted or UnsubstitutedDiacid Derivative to Form a Phenylhydroxylamine Adduct, Dehydrating toForm Substituted and Unsubstituted 2-Anilino-But-2-Ene Dicarboxylic AcidDerivative, Followed by Reaction with Vilsmeier Reagent to Form aQuinoline Derivative

The reaction descriptions which follow actually are preferredembodiments fall under the subject mauer described in Section I above,wherein the substituted or unsubstituted hydroxylamine is aphenylhydroxylamine which may have substituent groups on the aromaticring. ##STR32## wherein R₁, R₂, R₃, and R₄ are as described in SectionIII above; wherein R₁₃ is H, alkyl (preferably C₁ -C₆ straight orbranched, aryl (preferably phenyl or naphthyl), alkoxy, halogen, cyano,carboalkoxy, thioalkoxy, or CF₃.

The reaction conditions fall within the ranges previously provided inSection I and Section II above, and the following examples are providedfor purposes of illustration.

EXAMPLE 24 Synthesis of N-Phenylhydroxylamine

Prepared by the method of O. Kamm, Organic Synthesis, Vol. 1, pages445-447, the crude product was dissolved in ether filtered free ofsalts. The solvent was partially evaporated and hexane added. Theresultant white material was dried in vacuum oven mp. 82°-84° C.

EXAMPLE 25 Synthesis of Diethyl-N-Phenyl-N-Hydroxyaspartate

Diethylmaleate (7.7 g, 0.045 mole) was added to a mixture containing 5.0g (0.046 mole) N-phenylhydroxylamine in 7.66 g of absolute ethanol. Themixture was allowed to stir for 15 hours at room temperature. GCanalysis showed a trace of diethylmaleate remaining. 1.0 g of Norite wasadded along with 10 ml of additional ethanol. The mixture was allowed tostir for 10 minutes and then filtered free of the carbon. The carbon waswashed with additional ethanol. The filtrate was evaporated under highvacuum temperature to give an oil which crystallized upon cooling in adry ice/acetone bath. 11.9 g obtained after drying in vacuum desicatorat room temperature under high vacuum mp 50°-53° C.

EXAMPLE 26 Preparation of Diethyl-N-Phenyl-N-Hydroxyaspartate

A solution of diethyl maleate (20.65 g, 0.117 mol) in ethanol (25.0 g)was added dropwise to a solution of N-phenylhydroxylamine (14.6 g, 0.129mol) in ethanol (46.3 g). The reaction mixture was stirred at roomtemperature for an hour. The analysis of the reaction mixture by thinlayer chromatography indicated the completion of the reaction. Thereaction mixture was concentrated under reduced pressure to give thecrude product (37.46 g). The crude product was crystallized fromethylacetate-hexane (28.0 g, 85.0% yield).

EXAMPLE 27 Preparation of Diethyl 2-Anilinobut-2-ene-2,3-dicarboxylate

2.81 g (0.01 mole) of diethyl N-phenyl-N-hydroxy aspartate was dissolvedin 20 ml chloroform. To this solution was added 1.8 g (0.018 mole) oftdethylamine. To this solution, 1.0 g (0.0125 mole) acetyl chloride wasadded at room temperature, 22°-25° C. This mixture was allowed to stirfor 30 minutes before 1.8 g (.018 mole ) of triethylamine was added. Theresultant solution was heated to 55° C. for 4 hours. L.C. showsconversion to diethyl-N-phenylaminomaleate.

Example 28 Preparation of Diethyl 2-Anilinobut-2-ene-2,3-dicarboxylate

Triethylamine (4.02 g, 0.0398 mol) was added to a solution of diethylN-phenyl-N-hydroxyaspartate (10.1 g, 0.0357 mol) in dichloromethane (40mL) and stirred for 15 minutes. Acetic anhydrode (4.10 g, 0.040 mol) wasadded to reaction mixture over a period of 10 minutes. The reactionmixture was stirred at room temperature for an hour and refluxed foranother hour. The reaction mixture was concentrated under reducedpressure to give the crude product. The crude product was purified bydistillation to give diethyl 2-anilinobut-2-ene-2,3-dicarboxylate (7.8g, 74% yield). NMR (CDCl₃) δ1.03 (t, J 7.2 Hz, 3H), 1.29 (t, J 7.2, 3H),4.18 (m, 4H), 5.38 (s, 1H), 6.90-7.31 (m, 5H).

Example 29 Preparation of Diethyl Quinoline-2,3-dicarboxylate

The Vilsmeier reagent is prepared by adding Diphosgene (3.8 g, 19.3mmol) dropwise to a mixture containing dimethyl foramide (2.75 g, 37.7mmol) and dichloroethane (50 mL) while the temperature is maintainedbelow 20° C. using an ice bath. The reaction mixture is stirred for 45minutes at room temperature. Then a solution of diethyl2-anilinobut-2-ene-2,3-dicarboxylate (4.5 g, 17.1 mmol) indichloroethane (20 mL) is added dropwise to the reaction mixture andstirred at 80°-84° C. for 2.5 hours. The reaction mixture is cooled toroom temperature and diluted with ethyl acetate (250 mL). The reactionmixture is washed twice with brine (50 mL each) and once with water (100mL). The organic layer is concentrated under reduced pressure to givethe crude product which is purified by crystallization using ethylacetate and hexane to give diethyl quinoline-2,3-dicarboxylate (2.9 g,62% yield).

The above-described preferred embodiments are intended to beillustrative of the process of the present invention, as one skilled inthe art can introduce modifications which provide equivalent functionsand which are intended to fall within the scope of the present inventionas defined by the claims which follow.

We claim:
 1. A N-hydroxyaspartic acid derivative of the formula##STR33## where R₁ and R₂ are each independently ##STR34## where Z isOR₅ where R₅ is alkyl other than t-butyl, aryl, CN, arylalkyl; or NR₅ R₆where R₅ and R₆ are independently H, alkyl, aryl, arylalkyland R₃ and R₄are each independently H, alkyl, aryl, arylalkyl, ##STR35## where Z isas defined above, CN and halogen.
 2. The derivative of claim 1 which isdimethyl N-hydroxyaspartate.
 3. The derivative of claim 1 which isdiethyl N-hydroxyaspartate.
 4. The derivative of claim 1 which isdi-n-propyl N-hydroxyaspartate.
 5. The derivative of claim 1 which isdi-isopropyl N-hydroxyaspartate.
 6. The derivative of claim 1 which isdi-n-butyl N-hydroxyaspartate.
 7. The derivative of claim 1 which isdi-i-butyl N-hydroxyaspartate.
 8. The derivative of claim 1 which isN-hydroxyaspartonitrile.
 9. The derivative of claim 1 which is triethyl2-(N-hydroxyamino)ethanetficarboxylate.